Laboratory of Neurodegeneration and Neuroinjury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Neurotherapeutics. 2023 Sep;20(5):1405-1426. doi: 10.1007/s13311-023-01420-1. Epub 2023 Aug 18.
Accumulating data support a crucial role of gut microbiota in Parkinson's disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7 weeks) or aged mice (23 months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX) neurons and Ki67-positive (Ki67) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX neurons, as well as Ki67 cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.
越来越多的数据支持肠道微生物群在帕金森病（PD）中的关键作用。然而，肠道微生物群随年龄而变化，因此，其将以一种年龄依赖但未知的方式影响 PD。我们研究了粪便微生物群移植（FMT）预处理的作用，使用来自年轻（7 周）或年老（23 个月）小鼠的粪便微生物群，来研究 MPTP 诱导的 PD 模型。检查了运动功能、病理变化、纹状体神经递质、神经炎症、肠道炎症和肠道通透性。分析了肠道微生物群的组成和代谢物，即短链脂肪酸（SCFAs）。通过测量海马中双皮质素阳性（DCX）神经元和 Ki67 阳性（Ki67）细胞的数量来评估神经发生。还检查了海马中 Cd133 mRNA 的表达，Cd133 mRNA 是一种细胞干性标志物。接受来自年轻小鼠的 FMT 的小鼠表现出 MPTP 诱导的运动功能障碍，以及纹状体多巴胺（DA）、多巴胺能神经元和纹状体酪氨酸羟化酶（TH）水平降低。有趣的是，出乎意料的是，接受来自年老小鼠的 FMT 的小鼠表现出运动功能恢复和多巴胺能神经元和纹状体 5-羟色胺（5-HT）的拯救，以及 MPTP 挑战后 DA 代谢的减少。此外，它们表现出改善的代谢特征和粪便 SCFAs 数量减少。高通量测序显示，FMT 显著重塑了受体小鼠的肠道微生物群。例如，在接受年老微生物群（AM+MPTP 小鼠）的受体小鼠粪便样本中，阿克曼氏菌属和 Saccharimonas 属的水平升高，而 YM+MPTP 小鼠则没有。有趣的是，年轻微生物群和年老微生物群对神经炎症、肠道炎症或肠道通透性均无影响。值得注意的是，与 YM+MPTP 小鼠相比，AM+MPTP 小鼠的海马齿状回（DG）中的 DCX 神经元、Ki67 细胞和 Cd133 表达明显增加。这些结果表明，来自年老小鼠的 FMT 增强了神经发生，改善了 PD 模型小鼠的运动功能，并恢复了多巴胺能神经元和神经递质，这可能是通过增加神经发生来实现的。
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